Certain cardioactive oxido-bufadienolides

ABSTRACT

Cardioactive oxido-bufadienolides of the formula   WHEREIN R is hydrogen or lower acyl. Methods of making such compounds.

O v United States Patent [151 3,681,344 Radscheit et al. [451 Aug. 1, 1972 [54] CERTAIN CARDIOACTIVE OXIDO- OTHER PUBLICATIONS BUFADIENOLIDES Djerassi Steroid Reactions" pp. 598 (1963). [72] Inventors: Kurt Radscheit, Kelkhein/Taunus;

Ugrich s t?? g both Primary Examiner--l-lenry A. French 0 o elm aunus; erner A" m Fritsch, Neuenhain/Taunus; Ernst omey 8 Moms & Safiord Lindner, Frankfurt/Main, all of Ger- [57] ABSTRACT many [73] Assign: Farbwerke Hoechst Akfiem Cardroactrve oxido-bufadlenolldes of the formula gesellschaft vormals Meister Lucius & Bruning, Frankfurt/Main, Ger- 0 many I [22] Filed: Dec. 2, 1969 I [211 Appl. No.: 881,581

[30] Foreign Application Priority Data Dec. 5, 1968 Germany ..P l8 12 945.8 0

[52] US. Cl ..260/239.57, 260/999 [51] Int. Cl ..C07c 173/04 R0 [58] Field of Search ../Machine Searched Steroids 0 [5 6] References Cited wherein R is hydrogen or lower acyl. Methods of mak- UNITED STATES PATENTS mg Such compounds- 8 3,325,484 6/1967 Deghenghi ..260/239.55 2 Claims, N0 Drawings CERTAIN CARDIOACTIVE OXIDO- BUFADENOLIDES The. present invention relates to oxido-bufadienolides of the formula in which R represents hydrogen or an acyl group having one to five carbon atoms.

The present invention also relates to a process for the manufacture of the above-specified compounds of the formula I, wherein a. l4-anhydro-scillarenone (3-oxo-bufa-4, 14,20(2l) 22(23) tetraenolide) is reduced to yield 14-anhydro-scillarenine, this compound is acylated in 3- position, the 3a-acyloxy-compound thus obtained is reacted with N-bromic acid amides to yield 3aacyIoxy-4a, l4a-dihydroxy-5B, ISB-dibromo-bufadienolide, the latter compound is treated with agents that split ofi' HBr and, if desired to obtain the hydroxy compound, in the compounds obtained the 3a-acyl group is hydrolyzed, or

b. 3ahydroxy-l4, l5a-epoxy-bufa-4,20(2l),22(23) trienolide is treated with per-acids and, if desired to obtain an acyloxy compound, the product is subsequently acylated in the 3-position.

The individual steps of the process are shown in the following formula scheme:

U k l K,

J u l 0 R0 HO III (a) R=H III (b) Acyl .luBr a a O .H a... 0.

The individual process steps are carried out as is usual in steroid chemistry. For the reduction of the 3- keto group in II, metal hydrides, preferably sodium borohydride, lithium borohydride or lithium-tri- (tert.butoxy)-aluminum hydride are preferably used. The reaction of IlIb to yield the bromohydrin IV may be effected, for example, by treatment with N-bromoacetamide in dioxane in the presence of perchloric acid or by reaction with N-bromo-sulfonamides, preferably of aromatic sulfonic acids, for example N,N- dibromobenzene-sulfonamide, in weakly acid solution, for example in acetic acid. The bromohydrin lV need not be purified, it may be reacted directly to form the epoxide I. This reaction is effected in the usual manner with agents that split off HBr, for example organic bases such as pyridine, triethylamine, l,5-diazabicyclo-[4,3,0]-5-nonene or by means of aluminum oxide, silica gel, sodium acetate, or sodium carbonate.

In the manufacture of compound I starting from V by means of per-acids according to method (b), monoper-phthalic acid, per-benzoic acid or mono-chloroper-benzoic acid is preferably used.

Compound II can be prepared, starting from the 1 5ahydroxy desoxy-corticosterone known from the literature, by successive oxidation of the 2l-hydroxyl group, acetalization of the 21-aldehyde group that has formed, tosylation of the hydroxyl group in ISa-position, formation of the Al4-double bond by splitting off toluenesulfonic acid by means of lithium carbonate, protection of the 3-keto group by enol ester formation with orthoforrnic acid ester, formation of the 20,22-epoxide with trimethyl-sulfonium iodide/Nal-l, simultaneous separation of the acetal and enol-ester groups and cleavage of the epoxide ring with l-lBr, restoration of the 20,22- epoxide ring with triethylamine from the bromohydrin that has formed, selective condensation of the 2l-aldehyde group with carbomethoxymethyl-diethyl phosphonate to yield the 2l-carbomethoxymethane compound under conservation of the 3-keto group, isomerization of the 20,22-epoxide ring with borontrifluoride etherate to yield the 22-aldehyde and ring closure by means of aqueous-methanolic HCl to yield the compound II. This process is described in commonly owned copending US. Pat. application Ser. No. 735,964, filed by K. Radscheit et al. on June ll, 1968, now U. S. Pat. No. 3,574,198 granted 4/6/71.

Compound V can be prepared starting from II in known manner by reaction with N-bromo-acetamide/per-chloric acid to yield 14,15-bromohydrin,

separation of HBr and formation of the epoxide ring by treatment with a base, and reduction of the keto group in 3-position to a hydroxy group by means of lithiumtri-(tert.butoxy )-aluminum hydride.

The products obtained according to the present invention are novel and they are distinguished by a strongly positive inotropic action and, as a consequence thereof, by a strongly marked cardio-activity. They are, therefore, suitable for the medicinal treatment of heart damages, especially for the treatment of cardiac insufficiency and tachycardia. They are preferably administered in the form of tablets or dragees which contain, in addition to the active substances, the usual adjuvants and excipients, for example lactose, starch, tragacanth, etc.

The products of the invention may also be used as intermediates in the manufacture of medicaments, for example, by conversion of the 3-hydroxy compounds into corresponding derivatives such as esters or ethers, usual in steroid chemistry.

The following examples illustrate the invention:

EXAMPLE 1 3 SB-Ac etoxy-4,5a: l 4, l 5a-bis-oxido-bufa-20( 21 ),22( 23-dieno1ide a. 3B-Hydroxy-bufa-4,14,20(21),22(23) -tetraenolide (Illa) (Anhydro-scillarenin) A solution of 3.75 g of lithium-tri-(tert.butoxy)-aluminum hydride in 16.0 ml of absolute tetrahydrofurane was added dropwise, while stirring, at to --5 C to a solution of 518 mg of 3-oxo-bufa-4, 14,20(2l ),22( 23) -tetraenolide(11)in 52 ml of absolute tetrahydrofurane. Stirring was continued for 2%. hours at 3 to 0 C and then 20 ml of a 5 percent aqueous acetic acid were added slowly and dropwise. While cooling intensely, the whole was further stirred for 30 minutes. The reaction mixture was combined with water and extracted with methylene chloride. The methylene chloride was then removed by distillation, whereupon a crystalline residue was obtained which was recrystallized from a mixture of methylene chloride and ether with the addition of 2 drops of pyridine. 377 mg of compound Illa 14-anhydro-scillarenine) melting at 198 -200 C (Kofler block) were obtained.

Characteristic infrared bands: 3480, 1735 and 1715,

(shoulder) 1700, 1625,1530 cm.

Ultraviolet spectrum A 299 300 mu, 6 5450.

b. 3 B-Acetoxy-bufal, 1 4,20(2 l),22(23)-tetraenolide (IIlb) 250 mg of 3B-hydroxy-bufa-4,14,20(21),22( 23) -tetraenolide in a mixture of 4 ml of pyridine and 2 ml of acetic anhydride were allowed to stand for 17 hours at 20 C. The reaction mixture was poured into about 50 ml of water and, after standing for 17 hours, the oil that had separated was isolated by decantation. It was dissolved in methylene chloride, the solution was washed with water until neutrality, and the methylene chloride was removed by distillation. The 3fi-acetoxy-bufa- 4,14,20(21 ),22( 23) -tetraenolide was obtained in the form of a crude amorphous foam which was further reacted according to (c) without purification.

Characteristics infrared bands:

1530, 1230 cm, no hydroxyl band.

Ultraviolet spectrum: A 298 299 mu, s= 5050.

c. 3,B-Acetoxy-4,5,B: 14, 1513 -bis-oxido-bufa-20(2 1 ),22(23 -dienolide (I) A solution of 3fl-acetoxy-bufa-4,14,20( 21 ),22(23) tetraenolide (lllb) in 9 ml of dioxane was combined with 0.32 ml of glacial acetic acid, 2.7 ml of water and 210 mg of N,N-dibromo-benzene-sulfonamide and the whole was allowed to stand for 3 hours at 0 20 C in darkness. The reaction mixture was then poured into ml of water and extracted several times with methylene chloride. The extracts were washed with water and the solvents were removed by distillation under reduced pressure at a maximum temperature of 40 C. The remaining 3,8-acetoxy-4B,14B-dihydroxy-5 a, 15a-dibrorno-bufa-20(2l),22(23 )-dienolide (IV) was dissolved in a small amount of a mixture of methylene chloride and benzene (2: 1) and poured onto a column of aluminum oxide Woelm neutral, activity degree 11 (height 10 cm, diameter 2 cm). After allowing the column to stand for 20 minutes, elution was effected with a mixture of methylene chloride and benzene (2:1). A total of 300 ml of eluant was collected and, after removal of the solvents by distillation, 175 mg of compound I were obtained. After recrystallization Born a mixture of methylene chloride and ether, the compound was found to melt at 210 21 1 C.

Characteristic infrared bands: 1715-1740, 1625, 1530, 1235 cm, no hydroxyl band. Ultraviolet spectrum: h 298 299 u, e 5770.

EXAMPLE 2 3B-Acetoxy-4,5B: l4, 1 5B-bis-oxido-bufa-20( 21 ),22( 23) -dienolide A solution of 200 mg of 14,15B-oxido-scillarenin, (V) melting point 163 165 C, in 30 m1 of methylene chloride was combined with a solution of 290 mg of mono-per-phthalic acid in ether and the whole was allowed to stand for 5 hours at room temperature. The reaction solution was washed with a sodium bicarbonat solution and water, dried over sodium sulfate, and evaporated to dryness under reduced pressure. The crude product so obtained was dissolved in 5 ml of pyridine. The solution was combined with 2 ml of acetic acid anhydride and left for 18 hours at room temperature. Further working up was carried out as described in Example 10), The residue was recrystallized from a mixture of methylene chloride and ether. Melting point 210 21 1 C (Koller block).

Preparation of the starting compound 14,15B-oxidoscillarenin (V):

3-Oxo-l4,15B-oxido-bufa-4,20(21),22(23) -trienolide 14,15,8-Oxido-scillarenone):

200 mg of crude 3-oxo-l4B-hydroxy-15a-bromobufa-4,20(21),22(23) -trienolide (prepared by reaction of 14anhydro-scillarenone with perchloric acid and N-bromo-acetamide in dioxane at 15 C under exclusion of light) were chromatographed on acid aluminum oxide of activity degree H. Elution was effected with benzene and methylene chloride, the eluates were evaporated to dryness, and the residue was triturated with ether. Crystals melting at 169 172 C were obtained.

3fi-I-1ydroxy-14,15B-oxido-bufa-4,20(21 ),22( 23) trienolide 14,1 SB-Oxido-scillarenin) V:

3 ,68 1 ,344 5 6 130 mg of l4,l5B-o:ddo-sci1 larenone were dissolved in 10 ml of absolute tetrahydrofurane, the solution was combined at 10 C with a solution of 873 mg of LiA1H[OC(CH in 3.2 ml of tetrahydrofurane. After a reaction time of 1 hour at room tem- 5 perature, the mixture was poured into 80 ml of I water and filtered. The filtrate was extracted with chloroform and the extract was washed, dried and evaporated. The residue was dissolved hot in a 0 small amount of acetone and, after cooling, the 10 solution was combined with ether. 120 mg of product having a melting point of 163 165 c o 1 were obtained. Infrared spectrum! 3420-3460, 1700-1750, 1625, in which R represents hydrogen or an acyl group having 1535 cm". one to five carbon atoms.

Ultraviolet spectrum: 297 m 2. 3B-Acetoxy-4,5B-bis-oxide-bufa-20(2l ,22 23 What we claim is: dienolide.

1. An oxide bufadienolide of the formula 

2. 3 Beta -Acetoxy-4,5 Beta -bis-oxide-bufa-20(21),22(23)-dienolide. 